Planning Beyond the Petri Dish

The path to commercializing a breakthrough discovery is rarely a linear process. The orderly rationale of the scientific method is often overtaken by the random artistry of passion, personality, business culture, and sheer luck. Each plays a significant role in handicapping success or failure in that wending transition from bench to bedside. The story behind drug development is thus as interesting as a dime-store novel, except what is fiction in the second case is truth in the first—and always the developer's own dime is at stake.

Pfizer's crizotinib—a new targeted therapy that blocks progression of a genetic alternation in a subset of patients with non-small-cell lung cancer (NSCLC), extending survival well beyond the current standard of treatment—is revealing on two counts. The compound's extraordinarily fast development timeline shows that improvements in basic science around molecular biology are bringing more order to the process of moving from POC to confirmatory trials that conform to regulatory requirements for an accelerated NDA. At the same time, the path for crizotinib was littered with unforeseen risks, best exemplified by a chancy decision on clinical testing that, instead of yielding a medical breakthrough, could have shut the door on an entire field of investigation and potentially harmed Pfizer's reputation.

With reference to the speed of the science, several institutional drivers helped pull crizotinib out of the filing cabinet and into active development. First was a seemingly unrelated commitment by Pfizer to expand its research capabilities in Asia to accommodate the region's demand for data relevant to local clinical conditions. Governments like Korea were committing significant funds to facilitate home-grown research, particularly in oncology where the disease profile bore distinctive variations compared to the US. As a result, Pfizer began looking at how various tumor suppressing therapies based on the c-Met mutation that progresses metastasis could be leveraged against additional tumor types, including those prevalent in Asia.

"Crizotinib was just one of a broad panel of drug candidates we started looking at as a c-Met/HGFR inhibitor, from the same platform of discovery that led to Sutent, our multitargeted agent approved for the treatment of renal cell carcinoma and gastrointestinal stromal tumor," Darrel Cohen, senior director in the Pfizer Oncology Business Unit, tells Pharm Exec. "During the dose escalation part of the Phase I study of crizotinib in the US and Korea, we observed early responses in patients with advanced NSCLC. At the same time, we came across new academic research from Japan that identified how the anaplastic lymphoma kinase (ALK) fusion protein, normally associated with the growth of anaplastic large cell lymphoma, could be an oncogenic driver in a patient subset of NSCLC as well. Hence we went back and found that what these responding NSCLC patients shared was the presence of the ALK fusion gene. Given our strong local networks, we were able to connect the dots and apply this knowledge quickly to expand the Phase I clinical trial and initiate a Phase II study of crizotinib in ALK-positive NSCLC. And despite the limited test population evidence, we were able to take the risk of expanding the trial to focus on establishing how crizotinib suppresses tumor growth among those patients with advanced NSCLC harboring ALK rearrangements, a group that represents approximately 3 percent to 5 percent of the entire NSCLC patient population."

Pfizer contends that crizotinib is not only a potential therapeutic leader, but a benchmark in new ways to facilitate development partnerships across regions and markets. "It is an example of multisite codevelopment between East and West at a time when most such partnering has followed established pathways involving the US and Europe," Cohen says. "It speaks to our mindfulness that cancer is a global disease." Pfizer signals the success of this approach is exemplified by its joint simultaneous filing submissions on crizotinib to the FDA and the Japanese Ministry of Health Labor and Welfare in March of this year.

But there was also real risk in going global. The expanded trial proved more complicated than expected, involving extensive outreach to academic partners and regulatory authorities in Japan and Korea. In both groups there was concern about the generally precarious state of health among the candidate clinical trial population, most of whom were in the late stages of the disease. This was compounded by the cultural and medical practice gaps between the two countries that proved to be a potent challenge in defining and communicating the clinical trial protocol.

In one instance, Pfizer had to make a wrenching choice, says Oncology Business Unit Regional President for Asia, Jorge Puente. "We had a strong test candidate associated with one of our key academic research partners in Japan. The patient was at that point near death but our assessment was that getting him to the trial center in Korea might possibly prolong his survival and enhance the clinical relevance of the data. So we decided to pull out all the stops in registering the patient, including getting the Korean regulatory officials to accept his entry to the country, obtaining approval of the institutional trial review board, ensuring the patient's informed consent with the government oversight required under Japanese law, and arranging logistics and transport for a subject who by that time was on a respirator."

Puente notes that there was an acute awareness within Pfizer of the risks involved. "Consider if the patient had died while he was being MedEvac'd from Osaka to Korea. Our Japanese sponsoring professor would have been ostracized for pushing a sick man over the edge on behalf of a foreign commercial enterprise, while the competence of Korean medical research could have been tarnished. Most important, the Asian trial would have collapsed along with the strong test group we had assembled in Korea, which was based on both those countries' advanced understanding of the pharmacokinetics of the ALK rearrangement. By limiting the population to the US and Europe, we decidedly could not have achieved the rich response rate that allowed us to file globally with this early data." From a societal point of view, says Puente, the availability of this type of therapy to patients could have been set back years.

As it happened, the outcome was different. The 27-year-old patient survived the trip, was administered the drug, and within two days was off the respirator and walking unaided.

In a world where individual accountability has grown opaque, it is still true in science that reputations and livelihoods can be put on the line, often around statistically assumptive outcomes whose interpretation in the clinical setting can deliver life—or death—to thousands of patients. Says Puente, "Medicines research is not so much about institutions as it is about the passionate individual—the believer. They're the ones who face the biggest risks." That's why he's created a new incentive within Pfizer to recognize what he calls "Courage in Clinical Trials at Work." The first two recipients of the award are the Japanese researcher who discovered the link between ALK fusion genes and NSCLC and ensured that the sick test patient got to Korea, Dr. Hiroyuki Mano of Jichi Medical University; and the Korean researcher who accepted that patient into the Korean trial center, Professor Yung-Jue Bang of Seoul National University. They received the tribute at a ceremony on June 4, coinciding with the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, which heard further confirmation of their work in setting crizotinib as a potential treatment breakthrough.